Duke and Enzyvant Take Rare Immune Disease to School with New Therapy

A healthy baby enters the world with the cells it needs to build immunity. But in some cases, the cell levels are dangerously low. Rarer still are those born without the organ needed to properly develop these immune cells.

For babies who have this condition, called complete DiGeorge anomaly, even the common cold can become fatal. Without a healthy immune system, infection kills most children who have the disorder by age 2, says Mary Louise Markert, a professor of pediatrics at Duke University.

DiGeorge has no cure, but Markert is trying to give patients who have it a fighting chance. She has developed a regenerative medicine therapy intended to restore the immune system, and Duke has tested it in more than 80 patients so far. Enzyvant, the Cambridge, MA, company that licensed the rights to the therapy, is now preparing to file for FDA approval.

Immune system problems in newborns often have a genetic origin. In DiGeorge, that defect is a missing piece of chromosome 22. That can lead to a wide range of problems, including heart trouble and developmental delays, according to the Immune Deficiency Foundation. DiGeorge patients may also have low T cells, the frontline defenders of the immune system. These cells become fully developed in an organ called the thymus. In partial DiGeorge, patients have a small or poorly functioning thymus. In complete DiGeorge anomaly, the thymus is missing altogether.

Markert likens the thymus to a school. T cells start as stem cells in bone marrow, then travel through the blood to the thymus. In this thymus schoolhouse, she says, these T cell “students” mature into the immune cells able to distinguish between the body’s own tissue and invading organisms.

“When you have T cells that don’t go to school, they start attacking the baby,” she says.

Markert first encountered DiGeorge in 1992. A junior member of the Duke faculty in allergy and immunology at the time, she recalls receiving a phone call one night from a Tennessee pediatrician. He was treating a baby with DiGeorge and did not know what to do. Though Markert learned about DiGeorge in medical school, she had never treated the disease. She found a 1986 medical study describing thymus transplants. Of 26 babies who underwent the procedure, she says all but four died.

The Tennessee infant also died, Markert says. But she was motivated to find a way to treat other DiGeorge patients. Markert notes that attempts to transplant single thymus cells had also failed. She decided to fashion a different treatment from thymus tissue.

The first step is finding the tissue. Markert obtains it from infants 9 months or younger who are heart surgery patients at Duke. An infant’s thymus is large, and some of it covers the heart, Markert says. Instead of discarding the excess tissue, surgeons collect it—with parental consent—and set aside. If that tissue and the infant’s mother pass infection screening, the tissue then goes through a process to remove the cells of the donor that were preparing to become T cells. The end product is tissue that has the components and structure to function as thymus.

Surgery on the DiGeorge patient is the next step. But the thymus tissue isn’t transplanted at the site of the missing organ. Instead, slices of the tissue are embedded in pockets of the quadriceps, the large muscle on the front of the thigh. Markert credits an endocrine surgeon for the idea. The quadriceps has a good blood supply that provides oxygen and nutrients for the transplanted tissue, she says. The muscle’s large size also makes it easy to sample some tissue in a biopsy to assess the treatment. If the thymus is a schoolhouse, Markert says her transplants are school trailers—smaller teaching sites filling in for the closed school.

“We didn’t know if the stem cells would be able to find it,” she says. “It was amazing when we did the biopsy and it looked like normal thymus.”

Patients don’t reject the transplants because they lack T cells to mount an immune response, Markert says. The infant who received the first transplant procedure in 1993 is now a healthy 24-year-old woman, she says. To date, Duke has treated 84 DiGeorge patients.

Thymus tissue transplant results for the first 60 Duke patients were … Next Page »